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PLoS Genet. 2014 Jan 30;10(1):e1004140. doi: 10.1371/journal.pgen.1004140. eCollection 2014 Jan.

A chaperone-assisted degradation pathway targets kinetochore proteins to ensure genome stability.

Author information

1
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
2
Lehrstuhl für Funktionelle Genomforschung der Mikroorganismen, Heinrich-Heine Universität, Düsseldorf, Germany.
3
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America.
4
MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland, United Kingdom.

Abstract

Cells are regularly exposed to stress conditions that may lead to protein misfolding. To cope with this challenge, molecular chaperones selectively target structurally perturbed proteins for degradation via the ubiquitin-proteasome pathway. In mammals the co-chaperone BAG-1 plays an important role in this system. BAG-1 has two orthologues, Bag101 and Bag102, in the fission yeast Schizosaccharomyces pombe. We show that both Bag101 and Bag102 interact with 26S proteasomes and Hsp70. By epistasis mapping we identify a mutant in the conserved kinetochore component Spc7 (Spc105/Blinkin) as a target for a quality control system that also involves, Hsp70, Bag102, the 26S proteasome, Ubc4 and the ubiquitin-ligases Ubr11 and San1. Accordingly, chromosome missegregation of spc7 mutant strains is alleviated by mutation of components in this pathway. In addition, we isolated a dominant negative version of the deubiquitylating enzyme, Ubp3, as a suppressor of the spc7-23 phenotype, suggesting that the proteasome-associated Ubp3 is required for this degradation system. Finally, our data suggest that the identified pathway is also involved in quality control of other kinetochore components and therefore likely to be a common degradation mechanism to ensure nuclear protein homeostasis and genome integrity.

PMID:
24497846
PMCID:
PMC3907333
DOI:
10.1371/journal.pgen.1004140
[Indexed for MEDLINE]
Free PMC Article

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